Project summary/abstract While improvements in colorectal cancer (CRC) outcomes have been made over the past several decades, pronounced disparities in CRC incidence and mortality rates by race/ethnicity persist in the United States. In particular, CRC incidence and mortality rates among Alaska Native people (a particularly understudied population) are 124% and 148% higher, respectively, compared to the overall national rates, and among African Americans they are 21% and 39% higher, respectively. Our primary overarching goal is to reduce disparities in CRC mortality, particularly those experienced by Alaska Natives and African Americans, through improving approaches to identify patients with aggressive CRC at diagnosis and discovering novel potential therapeutic targets relevant to these populations. To address this goal, we will conduct a nested case-control study that utilizes highly clinically annotated tumor tissue specimens that are readily available from several resources. Cases are CRC patients who died of CRC within 5 years of their diagnosis, and controls are matched CRC patients who survived at least as long as the duration between diagnosis and death of the case that they are matched to. We will include four groups of patients defined by race/ethnicity: Alaska Native people, African Americans, Hispanics, and non-Hispanic whites with 70 cases of lethal CRC and 140 CRC controls from each group (total n=840). To discover novel prognostic markers, we will perform RNAseq analyses on RNA extracted from formalin-fixed paraffin embedded tumor material. The specific aims of this proposal are as follows: 1. Assess differences in gene expression profiles across four racial/ethnic groups and their relationships to selected CRC risk factors; 2. Discover predictors of CRC mortality across and within four different racial/ethnic groups; and 3. Characterize and evaluate differences in the immune and stromal cell populations in the tumor microenvironment associated with CRC mortality, overall and by race/ethnicity. This study will generate novel multi-ethnic high-dimensional data that we envision feeding into larger studies with translational goals focused on advancing novel intervention targets for primary and secondary prevention, and developing clinically useful predictors of poor CRC outcomes that can be used to guide clinical decision making. This study is designed to generate findings that will be of particular benefit to underserved populations as this work is aimed directly at reducing long-standing racial/ethnic disparities in CRC outcomes.